Although a large body of elegant work has developed on cellular and molecular aspects of drug abuse with the neurotransmitter dopamine at its core, the neuropeptides represent an area that has not been studied in relation to drug addiction. Neuropeptides can exert direct and/or indirect effects on the output of the dopaminergic network of the mammalian brain. The present project will focus on the role played by the neuropeptide substance P (and neurokinin A) on the development and/or expression of sensitized locomotor and neurochemical responses to cocaine. We hypothesize that these tachykinin peptides serve homeostatic functions within the basal ganglia to prevent excessive locomotor output in rodents sensitized to cocaine. The first and second specific aims will assess the effect of highly selective non-peptide neurokinin receptor antagonists on the development of progressive and enduring locomotor sensitization to cocaine. The third specific aim will examine the effect of these highly selective antagonists on the sensitized pattern of dopamine and glutamate release in dopaminergic terminal field areas of the caudate-putamen and the nucleus accumbens as well as in dopaminergic cell body areas of the midbrain substantia nigra compacta and the ventral tegmental area. The neurokinin receptor antagonists will be infused intracerebrally through the microdialysis probe. The fourth specific aim provides tissue peptide levels for substrate P and neurokinin A from rats sensitized to cocaine under progressive and enduring treatments. The data from this aim complements neuropeptide and receptor mRNA levels obtained from animals in aims I and II. These studies will provide strong behavioral and neurochemical evidence supporting a role for tachykinin peptides in sensitized responses to cocaine. An understanding of the neurobiology of sensitization to cocaine is relevant to the management of addiction in humans because sensitization is implicated as a mechanism sustaining drug-seeking behavior in humans addicted to cocaine and other drugs.